The human immunodeficiency virus (HIV) continues to annually infect millions individuals with most of these infections in developing countries where current anti- retroviral therapy is not readily available or affordable. However, prospects for an effective vaccine remain viable and realistic as HIV-specific antibodies have been isolated from infected individuals that are able to confer immune protection. Moreover, our understanding about how the different mature B cell populations mount antibody responses to foreign antigen has also advanced. Thus, we argue that current vaccine strategies should be able to selectively call upon these distinct B cell subsets to elicit an appropriate anti-viral antibody response. This application, therefore, considers the mechanisms by which distinct B cell subsets mount antibody responses to propose experiments designed to enhance the production of HIV neutralizing antibodies. A major goal of this proposal is to determine whether marginal zone B cells are able to participate in the antibody response to HIV and, if so, do they participate and, if not, can they be recruited to participate. To accomplish this goal in two specific aims, we rely on in vivo and in vitro mouse models of antibody production to molecularly and functionally define the HIV envelope-specific antibodies produced by different B cell subpopulations. Specific Aim 1 characterizes the phenotype of HIV envelope-specific B cells in na[unreadable]ve and immunized mice and the antibodies they produce with respect to polyreactivity, autoreactivity and neutralization capability. In Specific Aim 2 we center our attention on the toll-like receptors expressed by B cells and how agonists specific for these receptors alter, if at all, the type of B cells recruited into the HIV antibody response and the molecular and functional properties of the antibodies produced by these cells. Human and mouse marginal zone B cells are phenotypically and functionally similar, thus we consider the use of a mouse model to study the role of marginal zone B cells in the antibody response to HIV to be appropriate. More importantly, a comparable study of human marginal zone B cells is not feasible. Thus, these experiments investigating the principles of how distinct B cell populations respond to HIV in na[unreadable]ve and immunized mice will be directly relevant to human B cell biology and will provide significant insight into HIV vaccine design strategies. The need for an effective human immunodeficiency virus (HIV) vaccine is imperative as HIV continues to infect millions of individuals annually. This proposal outlines experiments that will define the contribution of different types of B lymphocytes in the production of antibodies specific for this virus. The information gained by this study will be directly relevant to considerations in HIV vaccine design. [unreadable] [unreadable] [unreadable]